Autosomal dominant polycystic kidney disease (ADPKD) affects l in 1,000 of the U.S. population. Previous linkage analyses have shown that 95% of the mutations affect the PKD1 gene on chromosome 16, band p13.3. The region containing the PKD1 gene has previously been mapped to a 500kb interval 3Mb from the tip of the chromosome. Twenty-three candidate genes have been identified within this region. Single-stranded conformational polymorphism analysis will be used to locate the mutations within these genes. Linkage disequilibrium studies of genetic linkage analysis will also be used to further refine the localization of the PKD 1 gene. Once the PKD1 gene has been identified, studies will be aimed at establishing the relationship between genotypes and phenotypes. A cloned gene will be used to express the PKD1 product in vitro, and to raise antibodies to the product so that its distribution of molecular interaction can be studied. Disruption of a gene on chromosome 14 in the mouse has been shown to cause a recessive polycystic kidney disease very similar to human recessive disease. We plan to study the human homolog of this gene and related genes to determine their involvement in a range of human cystic diseases of the kidney.